Olaf S. Andersen, M.D.

Professor of Physiology and Biophysics

  • Director, Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program

212-746-6350

1300 York Avenue, Room C-501 B
New York, NY 10065


Research Areas


Research Summary:

  • Energetic coupling between membrane proteins and their host lipid bilayer
  • Bilayer-mediated effects of biologically active molecules
  • Bilayer-dependent basis for cytotoxicity

Membrane protein function varies with changes in the composition (and physical properties) of the bilayer in which the protein is embedded, and the bilayer properties may change not only in response to changes in lipid composition but also in response to drug partitioning into the bilayer. This regulation of protein function involves both specific interactions between the protein and individual molecules (drugs or lipids) in the bilayer, and more general interactions between the protein and the lipid bilayer as a liquid crystal with physical properties (thickness, intrinsic curvature and the associated elastic moduli).

This is important for two interrelated reasons.  First, because the physico-chemical properties known to befall efficacious compounds — sufficient aqueous and lipid solubility — means that many, if not most, drugs are amphiphiles that partition into the bilayer/solution interface and thereby alter the bilayer’s physical properties.  Second, because integral membrane proteins (e.g., receptors, channels and transporters) undergo conformational changes that involve the proteins’ bilayer-spanning domains, which are coupled to the bilayer core through hydrophobic interactions. The bilayer adaptation to a membrane protein’s hydrophobic domain, the protein-induced bilayer deformation, has an energetic cost \(\left( \Delta G_{def}\right)\) that varies with changes in protein shape and bilayer properties. The free energy difference of a conformational change between protein states I and II \(\left( \Delta G^{I\rightarrow II}_{total}\right)\) thus will be the sum of contributions from rearrangements within the protein \(\left( \Delta G^{I\rightarrow II}_{protein}\right)\) and within the bilayer \(\left( \Delta G^{I\rightarrow II}_{bilayer} = \Delta G^{II}_{def} – \Delta G^{I}_{def}\right)\). For integral membrane proteins, with their irregular protein/bilayer boundary, there will be an additional contribution from the inevitable residual exposure of hydrophobic and polar residues \(\left( \Delta G^{I\rightarrow II}_{res} = \Delta G^{II}_{res} – \Delta G^{I}_{res}\right)\).

An extensive literature has demonstrated the regulation of cell and membrane protein function by changes in lipid bilayer composition. This bilayer-mediated regulation of membrane protein function is important because changes in lipid bilayer properties, e.g. due to the partitioning of drugs into the bilayer/solution interface, will alter the \(\Delta G^{I\rightarrow II}_{bilayer}\) and \(\Delta G^{I\rightarrow II}_{res}\)  contributions to \(\Delta G^{I\rightarrow II}_{total}\), providing a mechanism for the changes in protein function.  When such drug-induced changes in the bilayer contributions to \(\Delta G^{I\rightarrow II}_{total}\) become sufficiently large they produce global effects and, eventually, cytotoxicity.

Current experiments address the following questions:

  • What are the relation(s) between molecular structure and bilayer-modifying potency; can we predict the changes in bilayer properties (expressed as \(\Delta G^{I\rightarrow II}_{total}\)) based on a drug’s structure?
  • What are the biological consequences of drugs bilayer-modifying effects; at what point do they become cytotoxic; can we predict if a drug candidate is likely to have undesired effects?
  • What are bilayer-modifying effects of small peptides and proteins?
  • Can we develop experimental strategies for distinguishing between specific and bilayer-mediated regulation of membrane protein function?

Recent Publications:

  1. Sun, D, Peyear, TA, Bennett, WFD, Andersen, OS, Lightstone, FC, Ingólfsson, HI et al.. Molecular Mechanism for Gramicidin Dimerization and Dissociation in Bilayers of Different Thickness. Biophys. J. 2019;117 (10):1831-1844. doi: 10.1016/j.bpj.2019.09.044. PubMed PMID:31676135 .
  2. Park, S, Yeom, MS, Andersen, OS, Pastor, RW, Im, W. Quantitative Characterization of Protein-Lipid Interactions by Free Energy Simulation between Binary Bilayers. J Chem Theory Comput. 2019;15 (11):6491-6503. doi: 10.1021/acs.jctc.9b00815. PubMed PMID:31560853 .
  3. Andersen, OS, Nairn, AC, Palmer, LG, Shapley, RM. In Memoriam: David C. Gadsby, PhD. J. Gen. Physiol. 2019;151 (8):967-969. doi: 10.1085/jgp.201912400. PubMed PMID:31311825 PubMed Central PMC6683670.
  4. Gutzeit, VA, Thibado, J, Stor, DS, Zhou, Z, Blanchard, SC, Andersen, OS et al.. Conformational dynamics between transmembrane domains and allosteric modulation of a metabotropic glutamate receptor. Elife. 2019;8 :. doi: 10.7554/eLife.45116. PubMed PMID:31172948 PubMed Central PMC6588349.
  5. Kapoor, R, Peyear, TA, Koeppe, RE 2nd, Andersen, OS. Antidepressants are modifiers of lipid bilayer properties. J. Gen. Physiol. 2019;151 (3):342-356. doi: 10.1085/jgp.201812263. PubMed PMID:30796095 PubMed Central PMC6400527.
  6. Doktorova, M, Heberle, FA, Marquardt, D, Rusinova, R, Sanford, RL, Peyear, TA et al.. Gramicidin Increases Lipid Flip-Flop in Symmetric and Asymmetric Lipid Vesicles. Biophys. J. 2019;116 (5):860-873. doi: 10.1016/j.bpj.2019.01.016. PubMed PMID:30755300 PubMed Central PMC6400823.
  7. Falzone, ME, Rheinberger, J, Lee, BC, Peyear, T, Sasset, L, Raczkowski, AM et al.. Structural basis of Ca2+-dependent activation and lipid transport by a TMEM16 scramblase. Elife. 2019;8 :. doi: 10.7554/eLife.43229. PubMed PMID:30648972 PubMed Central PMC6355197.
  8. Zhang, M, Peyear, T, Patmanidis, I, Greathouse, DV, Marrink, SJ, Andersen, OS et al.. Fluorinated Alcohols' Effects on Lipid Bilayer Properties. Biophys. J. 2018;115 (4):679-689. doi: 10.1016/j.bpj.2018.07.010. PubMed PMID:30077334 PubMed Central PMC6104562.
  9. Dockendorff, C, Gandhi, DM, Kimball, IH, Eum, KS, Rusinova, R, Ingólfsson, HI et al.. Synthetic Analogues of the Snail Toxin 6-Bromo-2-mercaptotryptamine Dimer (BrMT) Reveal That Lipid Bilayer Perturbation Does Not Underlie Its Modulation of Voltage-Gated Potassium Channels. Biochemistry. 2018;57 (18):2733-2743. doi: 10.1021/acs.biochem.8b00292. PubMed PMID:29616558 PubMed Central PMC6007853.
  10. Harding, CV, Akabas, MH, Andersen, OS. In Reply to Sun et al. Acad Med. 2018;93 (2):150-151. doi: 10.1097/ACM.0000000000002036. PubMed PMID:29377855 .
  11. Posson, DJ, Rusinova, R, Andersen, OS, Nimigean, CM. Stopped-Flow Fluorometric Ion Flux Assay for Ligand-Gated Ion Channel Studies. Methods Mol. Biol. 2018;1684 :223-235. doi: 10.1007/978-1-4939-7362-0_17. PubMed PMID:29058195 PubMed Central PMC5971093.
  12. Lum, K, Ingólfsson, HI, Koeppe, RE 2nd, Andersen, OS. Exchange of Gramicidin between Lipid Bilayers: Implications for the Mechanism of Channel Formation. Biophys. J. 2017;113 (8):1757-1767. doi: 10.1016/j.bpj.2017.08.049. PubMed PMID:29045870 PubMed Central PMC5647621.
  13. Beaven, AH, Sodt, AJ, Pastor, RW, Koeppe, RE 2nd, Andersen, OS, Im, W et al.. Characterizing Residue-Bilayer Interactions Using Gramicidin A as a Scaffold and Tryptophan Substitutions as Probes. J Chem Theory Comput. 2017;13 (10):5054-5064. doi: 10.1021/acs.jctc.7b00400. PubMed PMID:28870079 PubMed Central PMC5634937.
  14. Herold, KF, Andersen, OS, Hemmings, HC Jr. Divergent effects of anesthetics on lipid bilayer properties and sodium channel function. Eur. Biophys. J. 2017;46 (7):617-626. doi: 10.1007/s00249-017-1239-1. PubMed PMID:28695248 PubMed Central PMC5693657.
  15. Harding, CV, Akabas, MH, Andersen, OS. History and Outcomes of 50 Years of Physician-Scientist Training in Medical Scientist Training Programs. Acad Med. 2017;92 (10):1390-1398. doi: 10.1097/ACM.0000000000001779. PubMed PMID:28658019 PubMed Central PMC5617793.
  16. O'Donnell, JP, Cooley, RB, Kelly, CM, Miller, K, Andersen, OS, Rusinova, R et al.. Timing and Reset Mechanism of GTP Hydrolysis-Driven Conformational Changes of Atlastin. Structure. 2017;25 (7):997-1010.e4. doi: 10.1016/j.str.2017.05.007. PubMed PMID:28602821 PubMed Central PMC5516944.
  17. Andersen, OS. Introduction to Biophysics Week: What is Biophysics?. Biophys. J. 2017;112 (9):2019. doi: 10.1016/j.bpj.2017.04.010. PubMed PMID:28494971 PubMed Central PMC5883561.
  18. Gotian, R, Raymore, JC, Rhooms, SK, Liberman, L, Andersen, OS. Gateways to the Laboratory: How an MD-PhD Program Increased the Number of Minority Physician-Scientists. Acad Med. 2017;92 (5):628-634. doi: 10.1097/ACM.0000000000001478. PubMed PMID:28441673 .
  19. Sodt, AJ, Beaven, AH, Andersen, OS, Im, W, Pastor, RW. Gramicidin A Channel Formation Induces Local Lipid Redistribution II: A 3D Continuum Elastic Model. Biophys. J. 2017;112 (6):1198-1213. doi: 10.1016/j.bpj.2017.01.035. PubMed PMID:28355547 PubMed Central PMC5376118.
  20. Beaven, AH, Maer, AM, Sodt, AJ, Rui, H, Pastor, RW, Andersen, OS et al.. Gramicidin A Channel Formation Induces Local Lipid Redistribution I: Experiment and Simulation. Biophys. J. 2017;112 (6):1185-1197. doi: 10.1016/j.bpj.2017.01.028. PubMed PMID:28355546 PubMed Central PMC5375002.
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